Journal of Ethnopharmacology 105 (2006) 34–38

Anti-inflammatory activity of cacalol and cacalone sesquiterpenesisolated from Psacalium decompositum�

M. Jimenez-Estrada a,∗, R. Reyes Chilpa a, T. Ramirez Apan a, Fernando Lledias b,Wilhem Hansberg b, Daniel Arrieta b, F.J. Alarcon Aguilar c

a Instituto de Quimica, Universidad Nacional Autonoma de Mexico, Coyoacan 04510, Mexico D.F., Mexicob Instituto de Fisiologia Celular, Universidad Nacional Autonoma de Mexico, Coyoacan 04510, Mexico D.F., Mexico

c Departamento de Ciencias de la Salud, D.C.B.S., Universidad Autonoma Metropolitana, Unidad Iztapalapa 09340, Mexico D.F., Mexico

Received 8 November 2004; received in revised form 10 September 2005; accepted 20 September 2005Available online 22 November 2005

Abstract

The hexane extract and two sesquiterpenic compounds, cacalol and cacalone, were isolated from the roots and rhizomes of Psacalium decom-positum. Then, their anti-inflammatory activity was evaluated in carrageenan-induced rat paw edema and 12-O-tetradecanoylphorbol-13-acetate(

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TPA)-induced ear edema. Indomethacin was used as the anti-inflammatory agent of reference.In the rat paw model of inflammation, both the hexane extract and the sesquiterpenes isolated from Psacalium decompositum showed a clear

ose-dependent inhibition of the carrageenan-induced edema (P < 0.05), with important differences among them during the temporal course of thenhibition. In the TPA-induced mouse ear edema all tested compounds showed anti-inflammatory activity in dose-dependent manner (P < 0.05). Inoth models, cacalone showed the most prominent anti-inflammatory activity.

We conclude that some of the beneficial effects attributed to Psacalium decompositum in traditional medicine can be related with the anti-nflammatory activity of cacalol and cacalone.

2005 Elsevier Ireland Ltd. All rights reserved.

eywords: Anti-inflammatory activity; Psacalium decompositum; Cacalia decomposita; Cacalol; Cacalone; Sesquiterpenic compounds

. Introduction

Psacalium decompositum (Gray) Rob et Brett. (syn. Cacaliaecomposita A. Gray, Asteraceae) has been traditionally usedn the northern region of Mexico and in the southwest regionf the United States as medicinal remedy. Both roots and rhi-omes of Psacalium decompositum have been utilized by theexican population against pains, rheumatism, renal, hepatic

nd gastrointestinal ailments, as well as an anti-diabetic rem-dy (Martinez, 1989). The anti-diabetic properties of this plantave been extensively studied (Alarcon et al., 2000). However,ttention has not been given to other healing properties.

Phytochemical studies revealed that Psacalium decomposi-um contains various sesquiterpenic compounds (furanoere-

� Contribution 2626 of the Instituto de Quımica, U.N.A.M.∗ Corresponding author. Tel.: +52 55 56 22 44 30; fax: +52 55 56 16 22 17.

E-mail address: manuelj@servidor.unam.mx (M. Jimenez-Estrada).

mophilanes), such as cacalol, cacalone, maturin, maturinoneand maturone, etc. (Romo and Joseph-Nathan, 1964; Correaand Romo, 1966). Cacalol (9-hydroxy-3,4,5-trimethyl-5,6,7,8-tetrahydronaphto (2,3-b) furan) and cacalone (Fig. 1) were foundto be the most abundant constituents of Psacalium decomposi-tum, and their presence has been demonstrated in the traditionalpreparation of this plant for medicinal purposes as an aqueousdecoction of roots and rhizomes (Alarcon et al., 1997), as wellas in other plants of the genus Cacalia (Naya et al., 1977; Omuraet al., 1978).

Cacalol and cacalone have been described as natural anti-oxidants (Krasovskaya et al., 1989). An inhibitory effect at thelevel of oxygen evolution in chloroplast thylakoids has beenreported for cacalol and derivatives (Lotina et al., 1991). More-over, cacalol has shown anti-microbial (Jimenez et al., 1992) andhypoglycemic activities (Inman et al., 1999). However, the anti-inflammatory activity, which could explain the use of Psacal-ium decompositum in some painful disorders and rheumaticdiseases, has not been studied with extracts or sesquiterpenic

378-8741/$ – see front matter © 2005 Elsevier Ireland Ltd. All rights reserved.

oi:10.1016/j.jep.2005.09.039

M. Jimenez-Estrada et al. / Journal of Ethnopharmacology 105 (2006) 34–38 35

Fig. 1. Natural sesquiterpenoids from Psacalium decompositum: (1) cacalol and(2) cacalone.

compounds. The aim of the present research was to study theanti-inflammatory activity of a hexane extract, as well as cacaloland cacalone, employing two distinct experimental models.

2. Materials and methods

2.1. Extraction and isolation of natural products

Ground roots and rhizomes (500 g) of Psacalium decom-positum (Herbarium IMSSM-Voucher Specimen 11489) wereextracted with petroleum ether at room temperature. The extract,concentrated after the removal of petroleum ether in vacuum wasfractionated with column chromatography on alumina (300 g)and eluted with petroleum ether (1). Cacalol was crystallizedfrom pentane–hexane to give white crystals (0.002%); mp91–92 ◦C; Rf 0.70. Cacalone was crystallized from petroleumether–acetone to give prisms (0.001%); mp 120 ◦C; Rf 0.25[�]D

+80. These data were corroborated with original compoundsand spectral data (IR, 1H NMR and 13C NMR) were comparedwith those reported in the literature, establishing that both com-pounds were cacalol and cacalone (Aguilar et al., 1996).

2.2. General experimental procedures

The 1H NMR spectra were recorded on Varian Gemini-2000and Varian VXR-300S of 200 MHz instruments. TetramethylsDNdtarpaiw

2

2U(t

(temperature 27 ± 1 ◦C) in a 12-h light:12-h dark cycle. Theywere fed with laboratory diet and water ad libitum. All experi-ments were carried out using four to six animals per group.

2.4. Drugs and dosage

Carrageenan lambda type IV, 12-O-tetradecanoylphorbol-13-acetate (TPA) and indomethacin were obtained from SigmaChemical Co. (St. Louis, MO, USA). In order to investigate thepharmacological activity, compounds were dissolved in 0.1 mlof DMSO and 0.9 ml of mineral oil for the carrageenan-inducedrat paw edema test, while for acute dermatitis test compoundswere suspended in acetone. Both vehicles were used as con-trol. Indomethacin was used as the anti-inflammatory agent ofreference and was dissolved in mineral oil or acetone.

2.5. Carrageenan-induced rat paw edema model

Male Wistar rats fasted for 12 h and with free access towater were studied. Before any treatment, the average volume(three or four measurements) of the right paw of each animalwas determined (Vo, basal volume) using a plethysmometer(Plethysmometer 7159, Ugo Basile). Immediately after, the testsubstances were administered per os. The control group receivedonly the vehicle. Sixty minutes later, paw edema was inducedbpo1tt

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ilane was used as internal reference and deuterochloroform andMSO were used as solvent. Infrared spectra were run with aicolet FT-IR 55X instrument using chloroform as solvent. MSata were recorded with a JEOL JMS-AX 505 HA mass spec-rometer. Column chromatography was carried out using Al2O3s support and petroleum ether as eluent. Thin layer chromatog-aphy (TLC) was performed on precoated silica gel 60 F254lates (0.2 mm thick, Merck) with the petroleum ether/ethylcetate (7:3) solvent system. TLC detection was made by spray-ng with a 1.0% ceric sulfate/H2SO4 solution. Melting pointsere obtained in a Fisher–Johns apparatus and are uncorrected.

.3. Experimental animals

Male Wistar rats and NIH mice, weighing 120–150 g and5–30 g, respectively, were provided by the Fisiologıa Celular,NAM, and approved by the Animal Care and Use Committee

PROY-NOM-087-ECOL-SSA1-2000). All animals were main-ained in standard laboratory conditions in the animal house

y subcutaneous injection of 0.1 ml carrageenan (0.1%) into thelantar surface of the right hind paw. The average volume (threer four measurements) of the paw of each rat (Vt) was measured, 3 and 5 h after the injection of the control substance, inflamma-ory agent or plant compounds. These individual records allowedo find out the variation of edema (Vt − Vo) for each group.

Percentages of inhibition (I%) in each treated groupas determined using the following formula: I% = 100 −

B × 100]/A, where A is the mean variation of edema (Vt − Vo)or the control group and B is the (Vt − Vo) for the treated groupsith extracts or compounds.

.6. Mouse ear edema

The assay of TPA-induced ear edema in mice was based onhe method described by Merlos et al. (1991). A group of six

ale NIH mice were anesthetized with Imalgen® and a solutionf 12-O-tetradecanoylphorbol-13-acetate (2.5 �g) dissolved inthanol (10 �l) was topically applied to both faces of the right earf the mice (5 �l each face). The left ear received only ethanol10 �l). After 10 min of TPA-treatment, solutions of 0.1, 0.5 or.0 mg of the test compounds, or the same doses of indomethacins reference, dissolved in 20 �l of acetone were applied to bothaces of the right ear (10 �l each face). Control animals receivednly acetone. Four hours later the animals were sacrificed byervical dislocation and a plug (7 mm diameter) was removedrom each ear.

The edematous response was measured as the weight differ-nce between the two plugs. The anti-inflammatory activity wasxpressed as percentage of the inhibition of edema in treatedice in comparison to control mice.

36 M. Jimenez-Estrada et al. / Journal of Ethnopharmacology 105 (2006) 34–38

Table 1Anti-inflammatory activity of the hexane extract and compounds isolated from Psacalium decompositum

Groups Dose (mg/kg) Percentage inhibition of edema

1 h 3 h 5 h

Indomethacin 2.5 29.2 ± 5.6 39.0 ± 4.4* 53.3 ± 3.7*

5.0 54.8 ± 3.8* 62.6 ± 7.3* 70.0 ± 5.9*

10 61.7 ± 4.5* 79.1 ± 3.9* 85.6 ± 5.4*

Root extract 2.5 27.3 ± 4.9 15.0 ± 2.8 28.1 ± 5.9*

5.0 48.8 ± 5.8* 35.0 ± 5.0* 46.9 ± 9.3*

10 66.7 ± 12.4* 50.0 ± 9.1* 53.1 ± 10.6*

Cacalol 2.5 41.8 ± 4.9* 20.4 ± 10.7 25.0 ± 10.85.0 54.9 ± 8.9* 24.5 ± 10.2 28.8 ± 10.9

10 62.6 ± 10.2* 27.6 ± 8.2* 38.8 ± 5.2*

Cacalone 2.5 20.9 ± 8.8 30.8 ± 5.8 41.9 ± 3.7*

5.0 30.7 ± 3.0 44.6 ± 4.3* 58.0 ± 6.2*

10 46.8 ± 3.0* 69.2 ± 2.5* 90.3 ± 6.1*

Effect of carrageenan-induced edema in rat paw. Each value represents the mean ± S.E.M. of four to five animals.* P < 0.05.

2.7. Statistical analysis

All data were represented as percentage inhibition of edema.Data were analyzed by one-way ANOVA followed by Dunnett’stest; P-values ≤ 0.05 were considered statistically significant(Tallarida and Murray, 1981).

3. Results

3.1. Carrageenan-induced edema model

Before injection of carrageenan, the basal values (Vo)ranged between 0.69 and 1.00 ml (0.87 ± 0.04 ml) and the meanvariations of edema (Vt − Vo) ± S.E.M. in control group forn = 12 were 1 h (0.17 ± 0.013 ml); 3 h (0.20 ± 0.012 ml) and 5 h(0.14 ± 0.016 ml). Edema inhibition in the compound-treatedgroups was calculated with reference to the control group val-ues and the percentage of inhibition obtained in each treatedgroup are shown in Table 1. Indomethacin showed a clear inhi-bition of the inflammation induced by carrageenan compared tocontrol group (P < 0.05). The hexane extract from roots and rhi-zomes of Psacalium decompositum at oral doses of 2.5 mg/kgcaused a minimal significant effect at 5 h, and at doses of5.0 and 10.0 mg/kg the effects were significant in all studiedpoints (P < 0.05). However, compared with the effect producedbaiodaeiibta

cacalone and indomethacin, which at 3 and 5 h increased theiractivity.

3.2. TPA-induced mouse ear edema

The effects of the topical application of root extract, cacalol,cacalone and indomethacin on TPA-induced mouse ear edemaare summarized in Table 2. The topical administration ofindomethacin significantly decreased the TPA-induced mouseear edema at all doses administered, compared to control group(P < 0.05). Hexane extract, cacalol and cacalone showed dose-dependent effects in this test. Hexane extract and cacalol causeda maximal inhibition at doses of 1 mg/ear, with an inhibitionratio of 39.2 and 45.4%, respectively, but clearly less than thatproduced by indomethacin (87.6%). However, cacalone at a

Table 2Anti-inflammatory activity of the hexane extract and compounds isolated fromPsacalium decompositum

Groups Dose (mg/ear) Weight of ears(mg) ± S.E.M.

Percentage inhibitionof edema

TPA + acetone – 16.62 ± 0.9 –Hexane extract 0.1 16.08 ± 0.7 3.3

0.5 11.6 ± 0.8 30.2**

1.0 10.1 ± 1.0 39.2*

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E

y indomethacin, this extract caused a minor effect, mainlyt 5 h. Although cacalol also showed anti-inflammatory activ-ty in this model, significant percentages of inhibition werebserved only at the beginning (1 h) in all the administeredoses. On the contrary, cacalone showed a dose-dependentnti-inflammatory activity in the carrageenan-induced rat pawdema test, equivalent to or higher than that produced byndomethacin in the majority of the studied points. Thus, anti-nflammatory activity of cacalol was different from that showedy the hexane extract and both were different in magnitude tohose produced by cacalone and indomethacin. Hexane extractnd cacalol showed stronger activity in the first hour than

acalol 0.1 15.36 ± 0.2 7.6**

0.5 10.1 ± 0.5 39.2**

1.0 9.08 ± 0.7 45.5**

acalone 0.1 13.42 ± 0.7 19.2**

0.5 6.96 ± 0.4 58.1**

1.0 2.98 ± 0.5 82.1**

ndomethacin 0.1 10.04 ± 0.9 39.6*

0.5 65.5 ± 0.4 60.53**

1.0 2.06 ± 0.3 87.61**

ffect on TPA-induced mouse ear edema.* P < 0.05.

** P < 0.001.

M. Jimenez-Estrada et al. / Journal of Ethnopharmacology 105 (2006) 34–38 37

dose of 1 mg/ear yielded 82.1% inhibition, comparable to thatof indomethacin.

4. Discussion

This work studied the potential of a hexane extract andtwo sesquiterpenic compounds (cacalol and cacalone) as anti-inflammatory agents in response to carrageenan and tetrade-canoylphorbol acetate.

The characteristic swelling of the paw that occurs in therat paw model of inflammation is due to edema formation. Inaccordance with Marsha-Lyn et al. (2002), inflammation occursthroughout three distinct phases: an initial phase mediated byhistamine and 5-hydroxytryptamine (up to 2 h); an intermedi-ate phase involving the activity of bradikinin and a third phase(3–6 h) with prostanoid synthesis induced by cyclooxygenase(COX) (Di Rosa, 1972; Perez et al., 2001).

The TPA has been reported to produce a long-lasting inflam-matory response associated with a marked cellular inflow and amoderate eicosanoid production (Rao et al., 1993). It is a power-ful protein kinase C activator (Huguet et al., 2000) whose edemais inhibited by both COX and 5-lypooxigenase inhibitors (Haraet al., 1992).

On the other hand, indomethacin is a non-steroidal anti-inflammatory drug (NSAID) with strong anti-inflammatoryand analgesic activity that is effective in the treatment ofrmigiaa

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In the TPA-test, hexane extract and cacalol also producedsignificant edema inhibition, causing a dose-dependent effect.The anti-inflammatory effect of cacalone in this model wasclearly higher than hexane extract and cacalol, with evident anti-inflammatory activity in all doses, similar to those produced bythe same doses of indomethacin.

On the other hand, cacalol and cacalone have also been con-sidered as natural anti-oxidants (Krasovskaya et al., 1989), withanti-microbial (Jimenez et al., 1992) and hypoglycemic activ-ities (Inman et al., 1999). In fact, several compounds isolatedfrom plants have showed similar biological activities: both anti-inflammatory and hypoglycemic activities (Roman et al., 1991;Maciel et al., 2000; Andrade and Wiedenfeld, 2001; Perez et al.,2001).

Although the basis of this relationship between both anti-inflammatory and hypoglycemic activities exhibited by theseplants is unclear, it is considered important to study the influenceof these compounds isolated from plants on inflammatory mark-ers of acute phase, such as tumor necrosis factor-�, interleukin-6,and reactive C protein, which have also been found to be abnor-mally increased in type 2 diabetes. Therefore, besides the inhibi-tion of COX, these compounds can have additional anti-oxidantand insulin-sensitizing properties that could be especially usefulin the treatment of type 2 diabetic patients (Sanchez and Kaski,2001; Pittas et al., 2004).

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heumatic and non-rheumatic conditions. In experimental ani-als, indomethacin is able to totally inhibit acute and chronic

nflammatory processes (erytema, edema, hyperalgesia andlaucoma) (Litter, 1992). It is also accepted that indomethacinnhibits COX, limiting therefore the biosynthesis of PGs,lthough it also has other activities that contribute to its ther-peutic effects (Insel, 1996).

The hexane extract, cacalol and cacalone showed significantnti-inflammatory action, evaluated by the reduction of edeman both experimental models: edema induced with carrageenanper os route) and edema induced with TPA (topical adminis-ration). In the carrageenan test, the hexane extract significantlyeduced the inflammation showing activity from the first mea-urement. According to these results, it can be suggested that theechanism of anti-inflammatory action of this extract occurs by

nterfering with the synthesis or liberation of histamine and PGediators.Cacalol and cacalone, two of the main constituents in hex-

ne extract of roots and rhizomes of Psacalium decomposi-um, showed distinct anti-inflammatory activity. Cacalol onlyeduced the inflammation at first hour after its administration,howing some connection with histamine function in the inflam-atory process. On the contrary, cacalone showed the highest

nti-inflammatory activity at the end of the carrageenan test5 h), indicating some association with PG inflammatory func-ion, and causing a very similar response to those inducedy indomethacin. The effect produced by cacalone probablynvolves other inflammatory mediators besides COX, such asistamine, 5-hydroxytryptamine, bradykinin or nitric oxide, allf which have been reported in carrageenan-induced edemaMarsha-Lyn et al., 2002).

. Conclusion

In conclusion, the hexane extract and sesquiterpenic com-ounds cacalol and cacalone clearly inhibited edema producedy carrageenan and TPA. Cacalone was found to be a potentnti-inflammatory agent in these tests. Although further experi-ents are required to establish these sesquiterpenoid compounds

s potential therapeutic agents, some of the beneficial effectsscribed in traditional medicine to roots and rhizomes of Psacal-um decompositum could be related with the anti-inflammatoryffects caused by cacalol and cacalone.

cknowledgment

This work was supported in part by grant IN206999 fromGAPA, National University of Mexico City.

eferences

guilar, M.M., Jimenez, M., Macias, R.N.A., Lotina, H.B., 1996. Electro-chemical properties of herbicides cacalol and its derivatives in proticand aprotics solvents by using cyclic voltammetry. Correlation withHill’s reaction activities. Journal of Agriculture and Food Chemistry 44,290–295.

larcon, F.J., Jimenez, M., Reyes, R., Gonzales, B., Contreras, C.C., Roman,R.R., 2000. Hypoglycemic activity of root water decoction, sesquiter-penoids, and one polysaccharide fraction from Psacalium decompositumin mice. Journal of Ethnopharmacology 69, 207–215.

larcon, F.J., Roman, R.R., Jimenez, M., Reyes, R., Gonzales, B., Flores,J.L., 1997. Effects of three Mexican medicinal plants (Asteraceae) onblood glucose levels in healthy mice and rabbits. Journal of Ethnophar-macology 55, 171–177.

38 M. Jimenez-Estrada et al. / Journal of Ethnopharmacology 105 (2006) 34–38

Andrade, A., Wiedenfeld, H., 2001. Hypoglycemic effect of Cecropia obtusi-folia on streptozotocin diabetic rats. Journal of Ethnopharmacology 78,145–149.

Correa, J., Romo, J., 1966. The constituents of Cacalia decomposita. A. Gray.Structure of maturin, maturinin, maturon, and maturinone. Tetrahedron 22,685–691.

Di Rosa, M., 1972. Biological properties of carrageenan. Journal of Pharmacyand Pharmacology 24, 89–102.

Hara, H., Sukamoto, T., Ohtaka, H., Abe, K., Tatumi, Y., Sairo, Y., Suzuki, A.,Tsukamoto, G., 1992. Effects of baicalein and �-tocopherol on lipid per-oxidation free radical scavenging activity and 12-O-tetradecanoylphorbolacetate-induced ear edema. European Journal of Pharmacology 221,193–198.

Huguet, A.I., Recio, M.C., Manez, S., Ginner, R.M., Rios, J.L., 2000. Effectof triterpenoides on the inflammation induced by protein kinase C acti-vators, neuronally acting irritants and other agents. European Journal ofPharmacology 410, 69–81.

Inman, D.W., Luo, J., Jolad, S.D., King, S.R., Cooper, R., 1999. Antihy-perglicemic sesquiterpenes from Psacalium decompositum. Journal ofNatural Products 62, 1088–1092.

Insel, A.P., 1996. Analgesicos-antipireticos y antiinflamatorios, y farmacosantigotosos. In: Hardman, J.G., Limbird, L.E., Molinoff, P.B., Ruddon,R.W., Goodman, G.A. (Eds.), Las bases farmacologicas de la terapeutica,ninth ed. McGraw-Hill Interamericana, Mexico, pp. 661–701.

Jimenez, M., Lozano, C., Valdes, M.J., Leon, J.R., Alarcon, G., Sveshtarova,B., 1992. Actividad antimicrobiana del cacalol y sus derivados. RevistaLatinoamericana de Quımica 23/1–22/4, 72.

Krasovskaya, N.P., Kulesh, N.I., Denisenko, V.A., 1989. Natural antioxidants.Furanoeremophilane from Cacalia roots. Khimiya Prirodnykh Soedinenii5, 643–646, Chemical Abstracts 1990; 112 95533u.

Litter, M., 1992. Compendio de Farmacologıa, fourth ed. El Ateneo,

L

M

Rao, N., 2000. Ethnopharmacology, phytochemistry and pharmacology:a successful combination in the study of Croton cajucara. Journal ofEthnopharmacology 70, 41–55.

Marsha-Lyn, M., Mckoy, G., Everton, T., Oswald, S., 2002. Preliminaryinvestigation of the anti-inflammatory properties of an aqueous extractfrom Morinda citrifolia (Noni). Proceedings of the Western Pharmacol-ogy Society 45, 76–78.

Martinez, M., 1989. Las plantas medicinales de Mexico. Botas, D.F. Mexico,Mexico.

Merlos, M., Gomez, L.A., Giral, M., Vencat, M.L., Garcia, R.J., Form, J.,1991. Effects of PAF-antagonists in mouse ear edema induced by severalinflammatory agents. British Journal of Pharmacology 104, 990–994.

Naya, K., Takai, K., Nakanishi, M., Omura, K., 1977. The sesquiterpenes ofCacalia species. II. Cacalol and the interconvertions of the constituents.Chemistry Letter 10, 1179–1182.

Omura, K., Nakanishi, M., Takai, K., Naya, K., 1978. The sesquiterpenesof Cacalia species: 8-oxocacalol and the stereochemistry of cacaloneepimers. Chemistry Letter 11, 1257–1260.

Perez, C., Herrera, D., Ortiz, R., Alvarez de Sotomayor, M., Fernandez, A.,2001. A pharmacological study of Cecropia obtusifolia Bertol aqueousextract. Journal of Ethnopharmacology 76, 279–284.

Pittas, A.G., Nandini, A.J., Andrew, S.G., 2004. Adipocytokines andinsulin resistance. Journal of Endocrinology and Metabolism 89, 447–452.

Rao, T.S., Currie, J., Shaffer, A.F., Isakon, P.C., 1993. Comparative evalua-tion of arachidonic acid (AA)- and tetradecanoylphorbol acetate (TPA)-induced dermal inflammation. Inflammation 17, 723–741.

Roman, R.R., Flores, J.L., Partida, G., Lara, A., Alarcon, F.J., 1991. Exper-imental study of the hypoglycemic effect of some antidiabetic plants.Archivos de Investigacion Medica 22, 87–92.

Romo, J., Joseph-Nathan, P., 1964. The constituents of Cacalia decomposita.

S

T

Argentina, pp. 608–638.otina, B., Roque, J.L., Jimenez, M., Aguilar, M., 1991. Inhibition of oxygen

evolution by cacalol and its derivatives. Zeitschrift fur Naturforschung46c, 777–780.

aciel, M., Pinto, C., Arruda, C., Pamplona, R., Vanderlinde, F.A., Lapa,A.J., Echevarria, A., Grynberg, N.F., Colus, S., Farıas, F., Luna, A.M.,

A. Gray. Structures of cacalol and cacalone. Tetrahedron 20, 2331–2337.anchez, A., Kaski, J.C., 2001. Diabetes mellitus, inflamacion y aterosclerosis

coronaria: perspectiva actual y futura. Revista Espanola de Cardiologıa54, 751–763.

allarida, R.J., Murray, R.B., 1981. Manual of Pharmacologic Calculations.Springer-Verlag, New York.